misoprostol solution versus oxytocin in term
pregnancy: randomized controlled trial
Indução do trabalho de parto por meio de solução oral titulada de
misoprostol versus oxitocina em gestação a termo: estudo controlado
randomizado
Abstract
PURPOSE: To evaluate the effectiveness and the safety of orally administered misoprostol in comparison to intravenously infused oxytocin for labor induction in term pregnant women.METHODS: Between 2008 and 2010, a total of 285 term pregnant women whom were candidate for vaginal delivery were assessed for eligibility to enter the study. Twenty ive patients were excluded for different reasons; and 260 included women were randomly assigned to one of the two groups according to the method of treatment, misoprostol or oxytocin. The misoprostol group received 25 µg every 2 hours for up to 24 hours for induction. The oxytocin group received an infusion of 10 IU which was gradually increased. The time from induction to delivery and induction to the beginning of the active phase and successful inductions within 12, 18, and 24 hours were recorded. The trial is registered at irct.ir, number IRCT2012061910068N1. RESULTS: Failure of induction, leading to caesarean section was around 38.3% in the oxytocin group and signiicantly higher than that of the misoprostol group (20.3%) (p<0.001). Despite the more prevalent failure in the oxytocin group, the mean time intervals from induction to active phase and labor of this group were both signiicantly less than the misoprostol group (10.1±6.1 and 13.2±7.7 versus 12.9±5.4 and 15.6±5.1 hours respectively, both p-values were <0.05). Maternal and fetal complications were comparable between groups except gastrointestinal symptoms which were encountered more frequently in the misoprostol (10.9 versus 3.9%, p=0.03).CONCLUSIONS: Misoprostol is a safe and effective drug with low complications for the induction of labor. Failure is seen less with misoprostol and caesarean sections are less frequently indicated as compared to oxytocin.
Clinical trial registered at Iranian Registry of Clinical Trials, number IRCT2012061910068N1.
Resumo
OBJETIVO:Avaliar a eicácia e segurança do misoprostol administrado por via oral em comparação à infusão de oxitocina para a indução do trabalho de parto em gestantes a termo. MÉTODOS: Entre 2008 e 2010, um total de 285 gestantes a termo candidatas para parto vaginal foram avaliadas quanto à eligibilidade para inclusão no estudo. Vinte e cinco pacientes foram excluídas por várias razões, e as 260 mulheres incluídas foram divididas aleatoriamente em dois grupos de acordo com o método de tratamento, misoprostol ou oxitocina. O grupo tratado com o misoprostol recebeu 25 µg cada 2 horas durante um máximo de 24 horas para indução. O grupo tratado com oxitocina recebeu infusão de 10 UI, que foi aumentada gradativamente. O tempo a partir da indução até o início da fase ativa e as induções bem-sucedidas dentro de 12, 18 e 24 horas foram registrados. O ensaio foi registrado em irct.ir, número IRCT2012061910068N1. RESULTADOS: A falha de indução levando à necessidade de cesariana foi de aproximadamente 38.3% no grupo tratado com oxitocina, sendo signiicativamente maior em relação ao grupo tratado com misoprostol (20,3%) (p<0,001). Apesar da falha mais prevalente no grupo tratado com oxitocina, os intervalos médios entre indução e fase ativa e trabalho de parto nesse grupo foram ambos signiicativamente menores em relação ao grupo tratado com misoprostol (10,1±6,1 e 13,2±7,7 versus 12,9±5,4 and 15,6±5,1 horas, respectivamente, sendo ambos os p-valores <0,05). Complicações maternas e fetais foram comparáveis entre grupos, com exceção dos sintomas gastrointestinais, que foram encontrados mais frequentemente no grupo tratado com misoprostol (10,9 versus 3,9%, p=0,03).
CONCLUSÕES: O misoprostol é droga segura e eicaz para a indução do parto, com poucas complicações. Falhas são menos observadas e cesáreas são indicadas menos frequentemente com o misoprostol em relação à oxitocina.
Ensaio clínico registrado no Iranian Registry of Clinical Trials, number IRCT2012061910068N1.
Study carried out at Shahid Beheshti University of Medical Sciences – Tehran, Iran.
1Department of Obstetrics and Gynecology, Shahid Beheshti University of Medical Sciences – Tehran, Iran.
Keywords Labor, induced/methods Misoprostol/administration & dosage Oxytocin/administration & dosage Pregnancy Pregnancy outcome
Palavras-chave Trabalho de parto induzido/métodos Misoprostol/administração & dosagem Oxitocina/administração & dosagem Gravidez Resultado da gravidez
Correspondence Aida Moeini, M.D. Department of Obstetrics and Gynecology, Tajrish Hospital, Tajrish Sq – Tehran, Iran.
Received 10/29/2012
Introduction
Labor induction is one of the most common proce-dures carried out worldwide for delivering mothers1. The
goal of labor induction is to stimulate uterine contrac-tions before the spontaneous onset of labor, resulting in vaginal delivery2. Uterine contractions and an appropriate
cervical ripening cervix are two important factors in labor contributing to good pregnancy outcomes3. The beneits
of labor induction must be weighed against the potential maternal and fetal risks associated with this procedure. When the beneits of expeditious delivery are greater than the risks of continuing the pregnancy, inducing labor can be justiied as a therapeutic intervention4.
Oxytocin and prostaglandins, such as misoprostol, are used for the induction of labor. The worldwide increase in use of this procedure during recent years necessitates a careful review of indications, resulted risks, and also beneits of labor induction especially regarding two main methods including oxytocin and misoprostol (a synthetic prostaglandin E1)5.
The usual method for inducing labor in our country is the use of oxytocin (Syntocinon) due to ethical-social concerns about the potential risk of abuse of misoprostol as an abortifacient drug. A number of trials have shown that misoprostol is more effective than oxytocin for labor induction in terms of reducing post-partum hemorrhage and time of induction. However, dosage of misoprostol, administration interval, administration route was different in published series6,7. According to some clinical
recom-mendation, based on limited or inconsistent evidence (level B), misoprostol at a dose of 50 µg every 6 hours, may be appropriate to induce labor8. Higher doses are
linked to a greater risk for uterine tachysystole with fetal heart rate (FHR) decelerations and other complications9.
Despite numerous reports on this issue, the question remains on eficacy and maternal/neonatal safety of oxy-tocin and misoprostol. The aim of the present study was, therefore, to evaluate the effectiveness and the safety of orally administered 25 µg of misoprostol every 2 hours in comparison to that of intravenously infused 10 units of oxytocin for labor induction in term pregnant women.
Methods
Study population
Between 2008 and 2010, a total of 285 term preg-nant women whom were candidate for vaginal delivery were assessed for eligibility to enter the study. All pa-tients provided an informed written consent; the study was approved by ethical committee of Shahid Beheshti University of Medical Sciences. Women were assured that they had the right to refuse to participate and/or
withdraw from the study at any time without being de-nied the standard clinical care. Twenty-ive patients were excluded for different reasons; 260 were included in the study. The inclusion criteria were women aged 18 years or older with a gestational age of 38 to 42 weeks and a singleton pregnancy who had request for elective termi-nation of pregnancy before 42 weeks of gestation or had medical indication for labor induction (hypertension and diabetes). Additional criteria for enrollment were birth weight of maximally 4.000 gram, normal fetal heart rate, cephalic presentation, lack of uterine contractures, and Bishop’s score of 6 or less. The exclusion criteria were lack of satisfaction for incorporation in the study, a positive history of uterine surgery including cesarean, intrauterine growth retardation (IUGR), oligohydramnios, placenta previa, umbilical cord prolapse, active herpes infection, symptoms of chorioamnionitis, hepatic or renal disease, non-reactive contraindications for prostaglandins use, contraindications for labor induction, and idiopathic vaginal bleeding.
As soon as the patients presented to delivery ward, baseline demographic and obstetric data including age, parity, body mass index (BMI), and past medical events were recorded and thereafter all the patients were evalu-ated for Bishop’s score by a senior resident physician.
Study design
This was a single center balanced randomized parallel-group study carried out in the Gynecology Department of Tajrish Hospital in Tehran, Iran. Patients were randomly assigned to one of two groups according to the method of treatment: oxytocin or misoprostol. Randomization was carried out using computer-generated simple random tables in a 1:1 ratio. It was not possible to blind the study participants and personnel from knowledge of which in-tervention a participant received because both methods were clearly different. Sample size was determined after consideration of type1 statistical error <5%; and type2 statistical error <20%.
Drug prescription method
Initiation of labor induction was the time at which the irst misoprostol dose was administered or the oxytocin infusion was started. In the oxytocin group, infusion rate of 2 mIU/min was prescribed for induction and gradually increased by 2 mIU/min every 15 minutes to a maximum dose of 36 mIU/min until adequate uterine contractions were attained.
was 300 µg. If the ideal pattern of uterine activites (at least 3 contractions per 10 minutes) was reached over 1 hour, misoprostol was no longer administered.
The practical strategies common to the administration of intravenous oxytocin or oral misoprostol solution were as follows: monitoring of FHR and intrapartum uterine activity was performed continuously; in the presence of any tachysystole or hypertonus, or changes in FHR as-sociated with tachysystole or hypertonus, infusion rate was decreased or stopped; intravenous magnesium sulfate (4 g over 30 minutes) could be given at the discretion of the physician if uterine hyperstimulation occurred.
The active phase was deined as achieving adequate uterine contractions with cervical dilatation greater than 3 cm. Contractions with regular intervals which resulted in progressive cervical dilatation, effacement were considered effective in induction of labor. Failure to progress was deined as the cervical dilation or fetal descent without any progress for 3 hours after entering the active labor phase as augmented by the agent.
In the absence of ideal uterine activites pattern after 24 hours of the irst drug administration, induction was considered to have failed. Cesarean section was performed if hyperstimulation syndrome or fetal hypoxia (thick me-conium and/or fetal monitoring alteration) were present and if induction was failed.
Adequate uterine contractions were deined as at least 3 contractions per 10 minutes and lasting 60–90 seconds. Tachysystole was deined as the presence of at least ive contractions in a 10-minutes interval. Hyperstimulation was deined as tachysystole or hypertonus with nonreas-suring FHR changes. FHR changes considered to be nonreassuring were late deceleration, severe variable deceleration, prolonged deceleration, tachycardia, or reduced FHR variability requiring intervention with either tocolytic or delivery.
All women were given standard postpartum care and discharged after 48 hours.
Outcome assessment
Outcome in terms of mode of delivery, time from induction to delivery and induction to the beginning of the active phase, and successful inductions within 12, 18, and 24 hours were all recorded as the primary parameters used to evaluate eficacy. The primary parameters used to evaluate adverse events were the rate of cesarean section and its indication and serious maternal complications such as uterine hyperstimulation, uterine rupture, and placental abruption.
The secondary parameters used to evaluate eficacy or adverse events included postpartum hemorrhage, abnormal changes in maternal vital signs, and gastrointestinal symp-toms (such as nausea, vomiting and diarrhea); regarding
to fetal and neonatal status and morbidity Apgar scores, fetal distress or fetal death and admission to the neonatal intensive care unit (NICU) were analysed.
Statistical analysis
Results were given as mean plus or minus SD. Statistical analysis was performed using the SPSS 16.0 statistical software package (SPSS Inc, Chicago, IL, USA). Time intervals were analyzed with Mann-Whitney U test and other data were analyzed with the χ2 for qualitative and
Student’s t-test for quantitative variables. A p-value of 0.05 was considered signiicant.
Results
Baseline characteristics
Two hundred and sixty consenting patients who ful-illed the entry criteria were enrolled in this study. Two hundred and ifty-six patients were able to complete the study and their data were included in the inal analyses. Demographic and clinical characteristics of patients are shown in the Table 1. There was no signiicant differ-ence between the groups regarding any of the studied parameters including age, nulliparity, gestational age, BMI, Bishop’s score, premature rupture of membranes, and indication for labor induction.
Induction results
The mean prescribed doses of misoprostol were 7.6±3. Both values of mean time from induction to ac-tive phase and induction to delivery were signiicantly shorter in oxytocin group than in misoprostol group (10.1±6.1 and 13.2±7.7 versus 12.9±5.4 and 15.6±5.1 hours respectively, both p-values were <0.05). The rate of vaginal deliveries within the irst 12 hours was com-parable between both groups. However, in comparison with the oxytocin group, patients in the misoprostol
Table 1. Demographic and clinical characteristics of patients
Demographic
Misoprostol (n=128)
Oxytocin
(n=128) p-value
n % n %
Nulliparity 68 53.1 73 57.1 0.5
Premature rupture of membranes (n) 3 2.3 5 3.9 0.7
Indication for labor induction 0.4
Request for termination of pregnancy 98 76.5 91 71
Hypertension 25 19.5 28 21.8
Diabetes 5 4 9 7.2
Gestational age (d) 280.6±4.5 282.8±5.3 0.4
BMI (kg/m2) 21.55±1.60 21.41±1.65 0.6
Bishop score 3.12±1.12 2.93±1.14 0.1
Age (y) 25.5±4.3 25.4±4.2 0.9
group had signiicantly higher rate of vaginal deliveries at time intervals of 18 and 24 hours during the study period (67.1, 79.7% versus 53.1, 61.7% respectively; all p-values were <0.05). There was no need for instrumental-assisted delivery in two groups. The most common indication for cesarean was lack of response to induction in both groups. Labor characteristics and delivery outcome data are summarized in Table 2.
Maternal complications
Except for the gastrointestinal symptoms, there were no statistically signiicant differences between the oxytocin and misoprostol patients groups in terms of other maternal complications (Table 3). In fact, gastrointestinal symptoms were observed more frequently in the misoprostol than in the oxytocin group (10.9 versus 3.9%, p=0.03); all of them were treated conservatively.
Neonatal outcomes
As shown in Table 4, the 1 and 5-Minute Apgar scores and birth weight were similar between the two groups (p=0.05). Fourteen patients (10.9%) in misopro-stol group and 16 subjects (12.5%) in oxytocin group had fetal tachycardia (p=0.07). Admission in neonatal intensive care unit was seen more frequently in oxytocin group (3.9%) than in misoprostol group (0.7%); however, this difference was not statistically signiicant (p=0.02). Only one patient (0.7%) in oxytocin group and none of the subjects in misoprostol group had meconium in amniotic luid (p=1.0). No maternal and neonatal deaths occurred in either group.
Discussion
Oxytocin and misoprostol are the most common drugs used for the induction of labor2. Many studies have
stated the safety and feasibility, eficacy, stability, and low cost of the misoprostol for induction of labor at term with an unfavorable cervix6,7,11. However, reported side
effects of this drug in comparison with oxytocin (such as nausea, gastrointestinal symptoms, uterine contraction abnormalities, abnormal heart rate tracing, and uterine rupture) could affect its usage in gynecologic practice12.
Optimal dosing of misoprostol that will achieve effec-tive induction without above mentioned side effects has been focused by many studies. For example, Hofmeyr et al. suggest an effective dose of 25 µg of misoprostol every 4 to 6 hours for reduction of complication rate. In our study, a dose of 25 µg which was repeated every 2 hours for up to 24 hours, was orally administered9.
It could be one of the limitations of this trial that the dose and administration interval were empirical. Hyperstimulation/tachysystole, fetal tachycardia and gastrointestinal symptoms were reported 18, 11 and 11% respectively in misoprostol group. Percentage of hyperstimulation/tachysystole in Saeed et al.2, Fonseca
et al.13, de Aquino et al.14 and Sanchez-Ramos et al.15
were 10, 15, 30 and 35 percent respectively. However, other investigators monitored the intrauterine pressure in misoprostol versus oxytocin groups and found that the average intensity of the contractions and the uter-ine tonus did not differ between them. The unaffected uterine tonus led to the theory that the tachysystole occurring with the use of misoprostol does not involve alterations in fetal vitality16.
The goal of labor induction is to stimulate uterine contractions resulting in vaginal delivery2. Our results
showed higher rate of vaginal deliveries in women un-dergoing labor induction with misoprostol compared with oxytocin (79.7 versus 61.7%). It is noticeable that there is no signiicant difference between the two
Table 2. Labor characteristics and delivery outcome data
Variable
Misoprostol (n=128)
Oxytocin
(n=128) p-value
n % n %
Vaginal delivery 122 79.7 79 61.7 <0.001
Within 12h 41 32.0 36 28.1 0.5
Within 18h 86 67.1 68 53.1 0.02
Within 24h 122 79.7 79 61.7 <0.001
Cesarean section 26 20.3 49 38.3 <0.001
Interval from induction to active
phase (hr) 12.9±5.4 10.1±6.1 0.002
Number of patients 126 114
Interval from induction to vaginal
delivery (hr) 15.6±5.1 13.2±7.7 0.01
Number of patients 122 79
Table 3. Maternal complications: comparison of labor induction with misoprostol or oxytocin
Variable
Misoprostol (n=128)
Oxytocin
(n=128) p-value
n % n %
Hyperstimulation/tachysystole 18 14.1 13 10.1 0.3
Postpartum hemorrhage 11 8.5 15 11.7 0.4
Blood transfusion 1 0.7 3 2.3 0.6
Placental abruption 1 0.7 1 0.7 1
Gastrointestinal symptoms 14 10.9 5 3.9 0.03
Table 4. Neonatal outcomes
Variable
Misoprostol (n=128)
Oxytocin
(n=128) p-value
n % n %
1-Minute Apgar ≤3 3 2.3 4 3.1 1.0
5-Minute Apgar ≤7 1 0.7 1 0.7 1.0
Neonatal intensive care unit
admission 1 0.7 5 3.9 0.2
Meconium staining 0 0 1 0.7 1.0
Fetal tachycardia 14 10.9 16 12.5 0.7
1. Zhang J, Yancey MK, Henderson CE. U.S. national trends in labor induction, 1989-1998. J Reprod Med. 2002;47(2):120-4. 2. Saeed GA, Fakhar S, Nisar N, Alam AY. Misoprostol for term
labor induction: a randomized controlled trial. Taiwan J Obstet Gynecol. 2011;50(1):15-9.
3. Beigi A, Kazemipour SM, Tabarestani H. Induction of labor in term pregnancy: sublingual versus vaginal misoprostol. Tehran Univ Med J. 2010;68(3):175-81.
4. Caughey AB, Sundaram V, Kaimal AJ, Cheng YW, Gienger A, Little SE, et al. Maternal and neonatal outcomes of elective induction of labor. Rockville: AHRQ; 2009. (AHRQ Evidence Report/Technology Assessment No. 176).
5. Balci O, Mahmoud AS, Acar A, Colakoglu MC. Comparison of induction of labor with vaginal misoprostol plus oxytocin versus oxytocin alone in term primigravidae. J Matern Fetal Neonatal Med. 2011;24(9):1084-7.
6. Chaudhuri P, Biswas J, Mandal A. Sublingual misoprostol versus intramuscular oxytocin for prevention of postpartum hemorrhage in low-risk women. Int J Gynaecol Obstet. 2012;116(2):138-42. 7. Ozsoy M, Ozsoy D. Induction of labor with 50 and 100 microg
of misoprostol: comparison of maternal and fetal outcomes. Eur J Obstet Gynecol Reprod Biol. 2004;113(1):41-4.
8. Allen R, O’Brien BM. Uses of misoprostol in obstetrics and gynecology. Rev Obstet Gynecol. 2009;2(3):159-68.
9. Hofmeyr GJ, Gülmezoglu AM, Pileggi C. Vaginal misoprostol for cervical ripening and induction of labour. Cochrane Database Syst Rev. 2010;(10):CD000941.
10. Alirevic Z, Weeks A. Oral misoprostol for induction of labour. Cochrane Database Syst Rev. 2009;(2):CD001338.
11. Tang OS, Ho PC. The pharmacokinetics and different regimens of misoprostol in early irst-trimester medical abortion. Contraception. 2006;74(1):26-30.
12. Goldberg AB, Greenberg MB, Darney PD. Misoprostol and pregnancy. N Engl J Med. 2001;344(1):38-47.
13. Fonseca L, Wood HC, Lucas MJ, Ramin SM, Phatak D, Gilstrap LC 3rd, et al. Randomized trial of preinduction cervical ripening: misoprostol vs oxytocin. Am J Obstet Gynecol. 2008;199(3):305.e1-5. 14. de Aquino MM, Cecatti JG. Misoprostol versus oxytocin for labor
induction in term and post-term pregnancy: randomized controlled trial. Sao Paulo Med J. 2003;121(3):102-6.
15. Sanchez-Ramos L, Kaunitz AM, Del Valle GO, Delke I, Schroeder PA, Briones DK. Labor induction with the prostaglandin E1 methyl analogue misoprostol versus oxytocin: a randomized trial. Obstet Gynecol. 1993;81(3):332-6.
16. Campos P G, Guzmán C S, Rodríguez A JG, Voto LS, Margulies M. Misoprostol, un análogo de la PGE1, para la inducción de parto de término: estudio comparativo y randomizado con oxitocina. Rev Chil Obstet Ginecol. 1994;59(3):190-5.
References
groups in percentage of vaginal deliveries within the irst 12 hours. One group of authors in a randomized study among 210 pregnant women compared the ef-fectiveness of orally administered 25 µg of misoprostol every 4 hours and intravenously infused 10 units of oxytocin. The cesarean section rate, latent period and period from induction to vaginal delivery were signii-cantly lower for the misoprostol group14. In another
study 120 patients were enrolled in misoprostol (57 cases) and oxytocin (63 cases) groups. Vaginal delivery occurred in 78.9 and 58.7% of misoprostol and oxyto-cin group respectively (p<0.05)17. Fonseca et al.13, by
performing a randomized trial did not show a statisti-cally signiicant difference between misoprostol and oxytocin group in term of vaginal delivery (87 versus 81%). Also, the total percentage of cesarean deliveries was not signiicantly different among these methods in Kramer’s study18.
The average time interval of drug prescription to vaginal delivery is related to the dose, route and administration interval of misoprostol or oxytocin in concurrence with favorable cervices for induction or previous administration of dinoprostone in pregnant women14. Most of these studies did not demonstrate
a difference in the interval from treatment to delivery between groups of misoprostol and oxytocin. However,
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induction to active phase and induction to delivery were signiicantly shorter in oxytocin group than in misoprostol group.
17. Escudero F, Contreras H. A comparative trial of labor induction with misoprostol versus oxytocin. Int J Gynaecol Obstet. 1997; 57(2):139-43.
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